Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.

Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.

Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin.

BACKGROUND: The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric (14)C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques. METHODOLOGY/PRINCIPAL FINDING: The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for (14)C content by accelerator mass spectrometry. The average plaque age (i.e. formation time) was 9.6±3.3 years. All but two plaques had formed within 5-15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p = 0.0014). Most plaques were echo-lucent rather than echo-rich (2.24±0.97, range 1-5). However, plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages (67.8±12.4 vs. 50.4±6.2, p = 0.00005; 57.6±26.1 vs. 39.8±25.7, p<0.0005, respectively), less collagen (45.3±6.1 vs. 51.1±9.8, p<0.05), and fewer smooth muscle cells (130±31 vs. 141±21, p<0.05) than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results show, for the first time, that plaque age, as judge by relative incorporation of (14)C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.

Multi-organ expression profiling uncovers a gene module in coronary artery disease involving transendothelial migration of leukocytes and LIM domain binding 2: the Stockholm Atherosclerosis Gene Expression (STAGE) study.

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10(-27 and-30)). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research.

Long-term outcome of infrainguinal percutaneous transluminal angioplasty.

PURPOSE: To evaluate the long-term outcome of infrainguinal percutaneous transluminal angioplasty (PTA). METHODS: Between 1991 and 1994, 77 patients (45 men; mean age 70 years, range 41-85) underwent infrainguinal PTA for occlusive disease. Patient records and angiographic examinations were reviewed to extract data to a patient register. A long-term (mean 9.3 years) follow-up examination of survivors was performed, including physical evaluation, walking impairment questionnaire (WIQ), and duplex ultrasound. RESULTS: Cumulative primary and secondary patency rates, respectively, were 81% and 86% at 1 year, 65% and 73% at 5 years, and 12% and 17% at 10 years. Patency rates were better for patients with claudication than critical ischemia (p=0.02). Stenoses had better primary patency than occlusions (p=0.001), but there was no difference between stenoses <2 cm versus >/=2 cm. At long-term follow-up, patients with patent vessels (50%) had better ankle-brachial indices (p=0.01) and less pain in their calves (p=0.04) compared to patients with non-patent vessels, but there was no difference in walking capacity or quality of life. Generalized femoral artery disease (p=0.03) and diabetes mellitus (p=0.03) predicted poor survival. CONCLUSIONS: Although the overall long-term patency of infrainguinal PTA is poor, the technique has a low morbidity and can be performed in selected patients with a reasonable long-term result.

Totally implantable subcutaneous port system versus central venous catheter placed before induction chemotherapy in patients with acute leukaemia-a randomized study.

A group of 43 adult patients with acute leukaemia (AL) were randomized to receive a double-lumen totally implantable subcutaneous port system (PORT, n=19) or a double-lumen central venous catheter (CVC, n=24) before induction chemotherapy. Six patients were excluded due to protocol violation ( n=4, CVC) and technical difficulties ( n=2, PORT). A standardized catheter record form was used for recording of catheter function, local infection and bleeding. The study was prematurely closed due to extensive subcutaneous bleeding after placement in five patients with a PORT. Intention to treat ( n=43) or per protocol (PP) analysis ( n=37) did not reveal a significant difference between the two groups with regard to catheter survival time (PP PORT, median 113 days, range 2-634 days; CVC, 55 days, 11-223 days). The number of positive blood cultures per 100 central venous access device days was significantly higher in the CVC group (median 3.6 per 100 days) than in the PORT group (0.9 per 100 days; P=0.02). In addition, the time to the first blood culture positive for coagulase-negative staphylococcus was shorter in the CVC group (median 14 days) than in the PORT group (52 days; P=0.02). Despite fewer infectious complications in the PORT group the use of a double-lumen CVC is advocated in patients with AL undergoing induction treatment due to the risk of extensive local bleeding after placement of the PORT.

The European experience with vascular injuries.

The rich and diverse heritage of the management of vascular injuries in the 45 independent European countries prevents the authors from revealing a uniform picture of the European experience, but some trends are clearly emerging. In countries with a low incidence of penetrating trauma and increasing use of interventional vascular procedures, the proportion of iatrogenic vascular trauma exceeds 40% of all vascular injuries, whereas on other parts of the continent, armed conflicts are still a major cause of vascular trauma. National vascular registries, mostly in the Scandinavian countries, produce useful, nationwide data about vascular trauma and its management but suffer still from inadequate data collection. Despite a relatively low incidence of vascular trauma in most European countries, the results are satisfactory, probably in most cases because of active and early management by surgeons on call, whether with vascular training or not, treating all kinds of vascular surgical emergencies. In some countries, attempts at developing a trauma and emergency surgical specialty, including expertise in the management of vascular injuries, are on their way.